Biosynthesis of the macrolide antibiotic, tylosin
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Tylosin is produced by Streptomyces fradiae via a combination of polyketide and deoxyhexose metabolism. Elucidation of the biosynthetic route to tylosin involved tracer incorporation studies and bioconversion analysis, with heavy reliance on the use of mutants of S. fradiae blocked in tylosin production [1-5]. The primary product of the Ty1G polyketide synthase is a 16-atom lactone (protylonolide, synonym tylactone) that subsequently acquires three deoxyhexose substituents (D-mycaminose, 6-deoxy-D-allose and L-mycarose) in a preferred but not obligatory order, although mycaminose is always added first. Thereafter, the deoxyallose moiety is converted to D-mycinose via bis-O-methylation. The polyketide lactone is also hydroxylated following attachment of the first sugar. This occurs at C-20 and C23, the latter being the site at which deoxyallose subsequently is added (Fig.1). Complementation of blocked mutants with cloned DNA fragments [6, 7] allowed the mapping of 13 tyl loci within the S. fradiae genome, alongside other attempts to identify the tylosin-production genes. Success in this regard eventually resulted from two convergent approaches instigated at Lilly Research Laboratories, Indianapolis.
KeywordsMacrolide Antibiotic Resistance Determinant Thioesterase Activity Lilly Research Laboratory Tylosin Production
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